Curr. Oncol., Volume 15, Issue 5 (October 2008) – 11 articles

Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase II–III clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors. Full article

The fluorinated pyrimidine 5-fluorouracil (5-FU) is an anticancer agent used in most adjuvant and palliative treatment regimens for colorectal cancer. Neurotoxicities are considered extremely rare side effects of 5-FU. Here, we report a case of 5-FU–induced encephalopathy, manifesting as seizures and delirium, in an era of oxaliplatin-containing chemotherapy. If ammonia levels are elevated, lactulose may be considered in the initial management of neuropsychiatric complications from 5-FU. Full article

Patients with chronic lymphocytic leukemia (CLL) are at a significantly increased risk of developing cutaneous squamous cell carcinoma (SCC), in part because of their impaired immunosurveillance. Here, we report the cases of 4 patients with CLL who had locally aggressive cutaneous SCC managed with radiotherapy for local recurrence following surgical excision. All tumours were located in the head-and-neck region. All patients initially achieved complete regression of disease; however, 2 had local recurrence a mean of 8 months after treatment completion. One patient died from progressive SCC. Our findings agree with the high rates reported in literature of multiple tumours, local recurrence, metastases, and mortality from SCC in patients with CLL. Radiotherapy plays an important role in patient management, and it is the recommended treatment modality when complete surgical excision of disease would result in anatomic and functional defects. Radiotherapy is often used in the case of local recurrence after one or more attempts at surgical excision. Dose escalation through intensity-modulated radiotherapy, hyperfractionation, or novel treatment techniques such as high-intensity focused ultrasound may be explored to improve local control of SCC lesions. To optimize patient outcomes, cutaneous SCC arising in patients with a history of CLL should be managed and followed in a multidisciplinary clinic, with regular skin surveillance and prompt treatment. Full article

Purpose: Reports investigating whether the response rates to palliative radiation therapy (rt) for painful bone metastases from gastrointestinal (gi) cancers are similar to rates for bone metastases from other primary cancer sites have been limited. The present study evaluated response rates for symptomatic bone metastases from gi cancers after palliative outpatient rt in the Rapid Response Radiotherapy Program (rrrp). Patients and Methods: We identified 69 patients with bone metastases from gi primaries who received palliative rt in the rrrp clinic during 1999–2006. We extracted records for 31 of these patients during 1999–2003 from an rrrp database that used the Edmonton Symptom Assessment Scale (esas). Record for the remaining 38 patients during 2003–2006 were extracted from an rrrp database that used the Brief Pain Inventory (bpi). Eligibility criteria for encryption in the two rrrp databases and for collection of patient demographic information (age, sex, primary cancer site, and Karnofsky performance status) were identical. Response rates for this cohort of metastatic gi patients were then compared to rates for 479 patients receiving palliative rt for bone metastases from other primary cancer sites. Pain scores from the esas and bpi and data on analgesic consumption were collected at baseline and by telephone follow-up at 4, 8, and 12 weeks after rt for all patients. Complete (cr), partial (pr), and overall (cr+pr) responses were evaluated according to International Consensus Endpoints. Results: Assessment of the 69 patients with metastatic gi cancers revealed cr, pr, and cr+pr rates of 18%, 42%, and 61% at 4 weeks; 22%, 35%, and 57% at 8 weeks; and 50%, 21%, and 71% at 12 weeks for evaluable patients. The 479 evaluable patients with metastatic cancer from other primary cancer sites had cr, pr, and cr+pr rates of 25%, 27%, and 51% at 4 weeks; 26%, 22%, and 48% at 8 weeks; and 22%, 29%, and 51% at 12 weeks. No statistically significant differences were observed in rt response rates for bone metastases from gi cancers than from other primary cancer sites. Conclusions: After palliative rt, bone metastases from gi cancers demonstrate response rates that are similar to rates for metastases from other primary cancer sites. Patients with symptomatic bone metastases from gi malignancies should be referred for palliative rt as readily as patients with osseous metastases from other primary cancer sites. Full article

Purpose: Symptom clusters (SCs) are a dynamic construct. They consist of at least 2 or 3 interrelated symptoms that may be a significant predictor of patient morbidity. In a previous study, we identified 2 SCs in patients with bone metastases: (1) An activity-related interference cluster; (2) A psychology-related interference cluster. These SCs may be clinically important in the pain and symptom management of patients with metastatic bone pain. It is therefore important to validate the reported SCs to determine if they hold true across similar patient populations. Patients and Methods: From February to September 2007, our study accrued 52 patients with bone metastases [29 men (56%), 23 women (44%); median age: 68.5 years (range: 39–87 years)] who were referred for palliative radiotherapy (RT). Prostate (31%), breast (29%), and lung (19%) were the most common primary cancer sites. Treatment arms ranged from single to multiple fractions, with most patients receiving a single 8-Gy fraction (77%) or 20 Gy in 5 fractions (21%). The most prevalent sites for RT were spine (42%), hips (17%), and pelvis (14%). Worst pain at the site of RT and functional interference scores were assessed using the Brief Pain Inventory (BPI), a multidimensional pain instrument that uses 11-point numeric rating scales. Patients provided their symptom severity scores on the BPI at baseline and at 4, 8, and 12 weeks post RT. At all time points, a principal component analysis with varimax rotation was performed on 8 items (worst pain and 7 functional interference items) to determine relationships between symptoms before and after RT for bone pain. Results: Two SCs were identified. Cluster 1 included worst pain and interference with general activity, normal work, and walking ability; cluster 2 consisted of interference with mood, sleep, enjoyment of life, and relations with others. Our statistical analysis produced varied results for the 2 clusters found in our previous investigation. These differences may be an indicator for the instability of SCs or may be a result of the fewer number of patients accrued in the present validation study. Conclusions: The SCs in our two studies were not identical for patients receiving palliative RT for symptomatic bone metastases. Another SC validation study should be conducted with a larger sample before a conclusion is drawn about the existence of an unstable phenomenon in SC research. Full article

The middle of the 20th century hailed the realization that patients with Hodgkin disease could be cured. Through the groundbreaking work of Vera Peters, patients with a localized form of the disorder, previously thought to be incurable, were shown to be cured by extended-field radiotherapy. This important observation, although not immediately accepted, opened the minds of physicians to take more positive investigative and therapeutic approaches. Peters also introduced and championed the concept of tumour staging in Hodgkin disease and the use of prognostic factors in clinical decision-making. This novel approach led to high cure rates with radiotherapy in localized disease and provided a scientific basis for the subsequent use of chemotherapy in disseminated disease, resulting in a very high cure rate in patients with all stages of Hodgkin disease. Full article

Background: Understanding the three-dimensional (3D) volumetric relationship between imaging and functional or histopathologic heterogeneity of tumours is a key concept in the development of image-guided radiotherapy. Our aim was to develop a methodologic framework to enable the reconstruction of resected lung specimens containing non-small-cell lung cancer (NSCLC), to register the result in 3D with diagnostic imaging, and to import the reconstruction into a radiation treatment planning system. Methods and Results: We recruited 12 patients for an investigation of radiology–pathology correlation (RPC) in NSCLC. Before resection, imaging by positron emission tomography (PET) or computed tomography (CT) was obtained. Resected specimens were formalin-fixed for 1–24 hours before sectioning at 3-mm to 10-mm intervals. To try to retain the original shape, we embedded the specimens in agar before sectioning. Consecutive sections were laid out for photography and manually adjusted to maintain shape. Following embedding, the tissue blocks underwent whole-mount sectioning (4-μm sections) and staining with hematoxylin and eosin. Large histopathology slides were used to whole-mount entire sections for digitization. The correct sequence was maintained to assist in subsequent reconstruction. Using Photoshop (Adobe Systems Incorporated, San Jose, CA, U.S.A.), contours were placed on the photographic images to represent the external borders of the section and the extent of macroscopic disease. Sections were stacked in sequence and manually oriented in Photoshop. The macroscopic tumour contours were then transferred to MATLAB (The Mathworks, Natick, MA, U.S.A.) and stacked, producing 3D surface renderings of the resected specimen and embedded gross tumour. To evaluate the microscopic extent of disease, customized “tile-based” and commercial confocal panoramic laser scanning (TISSUEscope: Biomedical Photometrics, Waterloo, ON) systems were used to generate digital images of whole-mount histopathology sections. Using the digital whole-mount images and imaging software, we contoured the gross and microscopic extent of disease. Two methods of registering pathology and imaging were used. First, selected PET and CT images were transferred into Photoshop, where they were contoured, stacked, and reconstructed. After importing the pathology and the imaging contours to MATLAB, the contours were reconstructed, manually rotated, and rigidly registered. In the second method, MATLAB tumour renderings were exported to a software platform for manual registration with the original PET and ct images in multiple planes. Data from this software platform were then exported to the Pinnacle radiation treatment planning system in dicom (Digital Imaging and Communications in Medicine) format. Conclusions: There is no one definitive method for 3D volumetric RPC in NSCLC. An innovative approach to the 3D reconstruction of resected NSCLC specimens incorporates agar embedding of the specimen and whole-mount digital histopathology. The reconstructions can be rigidly and manually registered to imaging modalities such as CT and PET and exported to a radiation treatment planning system. Full article

This paper reports two cases of acrometastasis to the hands. The first case involved a 78-year-old woman with a permeative osteolytic lesion in her proximal second metacarpal. A biopsy of this lesion suggested a diagnosis of non-small-cell lung carcinoma with secondary osseous metastasis. This was the first presentation of the woman’s primary diagnosis. A single 8-Gy fraction of palliative radiotherapy was delivered to the patient’s left hand. The treatment proved successful: the woman soon experienced pain relief and regained the use of her hand. The second case involved a 69- year-old woman with extensive lytic destruction involving the proximal two thirds of her third metacarpal. This patient had been diagnosed with carcinoma of the breast in 1990. She also received a single 8-Gy fraction of radiation, which improved both her pain and her hand mobility. An extensive review of the literature uncovered 257 previously reported cases of acrometastasis. Articles were analyzed based on age and sex of the patient, site of the primary carcinoma, metastatic locations within the hand and affected appendage or appendages, the treatment given, and the patient’s length of survival. Men were almost twice as likely to experience acrometastasis as women, and the median age of the patients overall was 58 years (range: 18 months–91 years). Lung, kidney, and breast carcinoma were the three most prevalent primary diagnoses reported in the literature. Cancers of the colon, stomach, liver, prostate, and rectum affected the remainder of the population. Overall, the right hand was more often host to the metastatic lesions. In addition, almost 10% of the patients experienced lesions in both hands. The third finger was the digit most affected by osseous metastases reported in the literature. Lesions of the thumb, fourth finger, second finger, and fifth finger were less commonly reported. The region of the digit most often affected within the patient population was the distal phalanx. The metacarpal bones, proximal phalanges, and middle phalanges comprised the remainder of the four most frequent acrometastatic sites. In the literature, single lesions were more prevalent than multiple bony lesions. Based on the reported cases, amputation appeared to be the preferred method of treatment. Radiation, excision, and systemic therapy were the next most frequently used treatments. Patient survival was not well documented within the literature. However, the median survival of patients in the reported cases was 6 months. Thus, our review suggested that a diagnosis of hand metastasis is an indication of poor prognosis. This report serves to emphasize the importance of properly diagnosing acrometastases. Identifying and effectively treating these metastases in a timely manner can lead to a dramatic improvement in a patient’s quality of life. Full article

Background: An estimated 20%–40% of cancer patients will develop brain metastases. Whole-brain radiotherapy (WBRT) is the standard treatment for patients with brain metastases. Although WBRT can reduce neurologic symptoms, the median survival following WBRT is between 3 and 6 months. Given this limited survival, it is important to consider quality of life (QOL) when treating patients with brain metastases. However, few studies have focused on QOL and improvement in patient-rated symptoms as primary outcomes. Objective: For an accurate measurement of the extent to which previous trials have utilized QOL tools to evaluate the efficacy of WBRT for treatment of brain metastases, we undertook a literature review to examine the common endpoints and QOL instruments used. Methods: We conducted a systematic search using the MEDLINE (1950 to December 2007) and Cochrane Central Register of Controlled Trials (4th quarter 2007) databases. Eligible studies investigated WBRT in one of the study arms. The following outcomes were included: median survival, overall survival, neurologic function, 1-year local control, and overall response; use of QOL instruments, performance status scales, and neurologic function assessments; and use of other assessment tools. Patient-rated QOL instruments were defined as those that strove to assess all dimensions of QOL; observer-rated performance instruments such as the Karnofsky performance status (KPS) were deemed to be performance scales. Results: We identified sixty-one trials that included WBRT as a treatment for brain metastases. Of these sixty-one trials, nine evaluated the treatment of a single brain metastasis, and fifty-two evaluated the treatment of multiple brain metastases. Although fifty-five of the trials employed a QOL instrument, few trials focused on QOL as an outcome. We found 23 different instruments used to evaluate QOL. The most commonly employed instrument was the KPS (n = 33), followed by various neurologic function classification scales (n = 21). A preponderance of the studies used 1 (n = 26, 43%) or 2 (n = 21, 34%) QOL instruments. A total of fourteen published trials on brain metastases included an evaluation of the study population’s QOL. Those trials included three that used the Functional Assessment of Cancer Therapy–General scale and Brain subscale instrument, three that used the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (C30) and the Brain Cancer Module 20 instrument, two that used study-designed QOL instruments, one that used the Edmonton Symptom Assessment Scale, two that used the Spitzer Quality of Life index, and three that used the KPS to evaluate QOL. Some trials reported deterioration in QOL after WBRT in patients with poorer prognosis; other trials detected an improvement in QOL after WBRT in patients with better prognosis. Conclusions: To date, fourteen trials in brain metastases that have included an evaluation of the study population’s QOL have been published. Although some studies showed that certain parameters of QOL deteriorate after WBRT, other studies showed that QOL in patients with better prognosis is improved after WBRT. Because a standard, validated QOL instrument has not been used for this patient population, a comparison of findings concerning QOL between the studies is difficult. The present review emphasizes the need to include QOL measures in future WBRT clinical trials for brain metastases. Full article